TY - JOUR
T1 - Ovarian cancer cell-derived lysophosphatidic acid induces glycolytic shift and cancer-associated fibroblast-phenotype in normal and peritumoral fibroblasts
AU - Radhakrishnan, Rangasudhagar
AU - Ha, Ji Hee
AU - Jayaraman, Muralidharan
AU - Liu, Jinsong
AU - Moxley, Katherine M.
AU - Isidoro, Ciro
AU - Sood, Anil K.
AU - Song, Yong Sang
AU - Dhanasekaran, Danny N.
N1 - Funding Information:
This research was supported by National Institutes of Health grant GM103639 (to D.N. Dhanasekaran & J.H. Ha); National Research Foundation of Korea BK Program grant 2009-0093820, the BK21 Plus Program grant 5256-20140100 (Y.S. Song); and Grants from Stephenson Cancer Center, OUHSC, Oklahoma City, OK; Mary K. Chapman Foundation Grant Award for Stephenson Cancer Center-MD Anderson Collaborative Research (D.N. Dhanasekaran, K.M. Moxley, J. Liu, and A.K. Sood). Technical assistance by Dr. Chiara Vidoni and Ms. Alessandra Ferraresi, Università del Piemonte Orientale, is gratefully acknowledged. Tissue acquisition and pathology services, provided by the Biorepository Core and the Biospecimen Pathology Core of the Stephenson Cancer Center, were supported by the National Institute of General Medical Sciences Grant P20 GM103639 and the National Cancer Institute Grant P30CA225520 of the National Institutes of Health.
Funding Information:
This research was supported by National Institutes of Health grant GM103639 (to D.N. Dhanasekaran & J.H. Ha); National Research Foundation of Korea BK Program grant 2009-0093820 , the BK21 Plus Program grant 5256-20140100 (Y.S. Song); and Grants from Stephenson Cancer Center , OUHSC, Oklahoma City, OK; Mary K. Chapman Foundation Grant Award for Stephenson Cancer Center-MD Anderson Collaborative Research (D.N. Dhanasekaran, K.M. Moxley, J. Liu, and A.K. Sood). Technical assistance by Dr. Chiara Vidoni and Ms. Alessandra Ferraresi, Università del Piemonte Orientale, is gratefully acknowledged. Tissue acquisition and pathology services, provided by the Biorepository Core and the Biospecimen Pathology Core of the Stephenson Cancer Center, were supported by the National Institute of General Medical Sciences Grant P20 GM103639 and the National Cancer Institute Grant P30CA225520 of the National Institutes of Health .
Publisher Copyright:
© 2018 Elsevier B.V.
PY - 2019/2/1
Y1 - 2019/2/1
N2 - Cancer-associated fibroblasts (CAFs) play a critical role in cancer progression, metastasis, and therapy resistance. Molecular events that confer CAF-phenotype to predecessor-cells are not fully understood. We demonstrate here that the ovarian cancer cell-conditioned medium (OCC-CM) induces CAF-phenotype in MRC5 lung-fibroblasts and it can be mimicked by LPA. While OCC-CM and LPA stimulated the expression of cellular CAF-markers by 3-days, they induced aerobic glycolysis, a metabolic marker for CAF, by 6 hrs. OCC-CM/LPA-induced glycolysis in lung (MRC5) as well as ovarian fibroblasts (NOF151) was inhibited by the LPA-receptor antagonist, Ki16425. Ovarian cancer patient-derived ascitic fluid-induced aerobic glycolysis in both NFs and Ovarian CAFs and it was inhibited by Ki16425. Further analysis indicated that LPA upregulated HIF1α-levels and the silencing of HIF1α attenuated LPA-induced glycolysis in both NOFs and CAFs. These results establish LPA-induced glycolytic-shift as the earliest, potentially priming event, in NF to CAF-transition. These findings also identify a role for LPA-LPAR-HIF1α signaling-hub in the maintenance of the glycolytic-phenotype in CAFs. Our results provide evidence that targeted inhibition of LPA-mediated metabolic reprogramming in CAFs may represent an adjuvant therapy in ovarian cancer.
AB - Cancer-associated fibroblasts (CAFs) play a critical role in cancer progression, metastasis, and therapy resistance. Molecular events that confer CAF-phenotype to predecessor-cells are not fully understood. We demonstrate here that the ovarian cancer cell-conditioned medium (OCC-CM) induces CAF-phenotype in MRC5 lung-fibroblasts and it can be mimicked by LPA. While OCC-CM and LPA stimulated the expression of cellular CAF-markers by 3-days, they induced aerobic glycolysis, a metabolic marker for CAF, by 6 hrs. OCC-CM/LPA-induced glycolysis in lung (MRC5) as well as ovarian fibroblasts (NOF151) was inhibited by the LPA-receptor antagonist, Ki16425. Ovarian cancer patient-derived ascitic fluid-induced aerobic glycolysis in both NFs and Ovarian CAFs and it was inhibited by Ki16425. Further analysis indicated that LPA upregulated HIF1α-levels and the silencing of HIF1α attenuated LPA-induced glycolysis in both NOFs and CAFs. These results establish LPA-induced glycolytic-shift as the earliest, potentially priming event, in NF to CAF-transition. These findings also identify a role for LPA-LPAR-HIF1α signaling-hub in the maintenance of the glycolytic-phenotype in CAFs. Our results provide evidence that targeted inhibition of LPA-mediated metabolic reprogramming in CAFs may represent an adjuvant therapy in ovarian cancer.
KW - Cancer-associated fibroblasts
KW - Glycolysis
KW - HIF1
KW - Hypoxia-inducible factor 1
KW - Lysophosphatidic acid
KW - Ovarian-cancer
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UR - http://www.scopus.com/inward/citedby.url?scp=85057808609&partnerID=8YFLogxK
U2 - 10.1016/j.canlet.2018.11.023
DO - 10.1016/j.canlet.2018.11.023
M3 - Article
C2 - 30503552
AN - SCOPUS:85057808609
SN - 0304-3835
VL - 442
SP - 464
EP - 474
JO - Cancer Letters
JF - Cancer Letters
ER -